pH-sensitive MRI demarcates graded tissue acidification during acute stroke ― pH specificity enhancement with magnetization transfer and relaxation-normalized amide proton transfer (APT) MRI
Graphical abstract
Introduction
Amide proton transfer (APT) MRI is promising in capturing tissue pH changes in disorders such as acute ischemia and tumor by depicting the chemical exchange saturation transfer (CEST) effect between the endogenous protein/peptide amide protons and bulk water (McVicar et al., 2014, Sheth et al., 2012, Sun and Sorensen, 2008, Sun et al., 2012, Ward et al., 2000, Zhou et al., 2003). As tissue acidosis has been postulated as a surrogate metabolic biomarker, pH imaging augments conventional MR spectroscopy (MRS)-based techniques by refining tissue classification (Chang et al., 1990, Moon and Richards, 1973, Ojugo et al., 1999). Indeed, it has been shown that pH MRI detects metabolic penumbra, complementing the commonly used perfusion and diffusion MRI for mapping metabolic disruption following ischemia (Harston et al., 2015, Sun et al., 2011b, Sun et al., 2007c).
APT MRI is often measured using the magnetization transfer (MT) asymmetry (MTRasym) to compensate for RF spillover effect. In addition to pH, MTRasym however, is susceptible to semisolid magnetization transfer, nuclear overhauser effect (NOE) and relaxation (Heo et al., 2016, Jokivarsi et al., 2007, Sun et al., 2005, Woessner et al., 2005). Particularly, because MT and NOE contributions are asymmetric, MTRasym image is of limited pH specificity (Desmond and Stanisz, 2012, Heo et al., 2016, Sun et al., 2007b, Zhou et al., 2004, Zong et al., 2014). Although normal brain white (WM) and gray matter (GM) have similar intracellular pH (Back et al., 2000), they appear drastically different in the pH-weighted MTRasym image. Consequently, it has been very challenging to resolve graded metabolic disruption within the heterogeneous perfusion/diffusion lesion mismatch (Harston et al., 2015, Sun et al., 2007c). Jin et al. estimated that the mobile amide proton concentration is about 10–20% higher in brain GM than WM (Jin et al., 2013). Concurrently, brain GM longitudinal relaxation time is slightly longer than that of WM (de Graaf et al., 2006). Hence, we postulated that concomitant saturation transfer effects (i.e., MT and NOE) and bulk water relaxation variation across the brain may contribute substantially to the pH-independent heterogeneity in the routine MTRasym image, correction of which could improve the pH specificity of APT MRI. Because the relaxation and MTR changes during acute stroke are relatively small, we proposed magnetization transfer and relaxation-normalized APT (MRAPT) analysis for acute stroke imaging, in complementary to routine stroke MRI for improved stratification of graded metabolic injury.
Section snippets
Theory
The in vivo MTRasym can be generally described bywhich includes pH-sensitive APT effect (APTR) and an intrinsic MTR asymmetry shift (MTR'asym) not related to pH. The APT effect (APTR) can be described by an empirical solution (Sun and Sorensen, 2008)where α is the amide proton labeling coefficient, σ is the bulk water spillover factor, famide and kamide are labile amide proton concentration and pH-dependent exchange rate,
Animal stroke model
The animal experiments have been approved by the Institutional Animal Care and Use Committee. Adult male Wistar rats (Charles River Laboratory, Wilmington, MA) were anesthetized with 1.5–2.0% isoflurane/air mixture throughout the study. Heart rate and oxygen content of blood (SpO2) were monitored online (Nonin Pulse Oximeter 8600, Plymouth, MN), and body temperature was maintained by a circulating warm water jacket. Ten normal (n = 10) and twenty acute stroke rats (n = 20) following the standard
Results
Fig. 1a simulates the experimental factor (i.e., α*(1-σ), B1 = 0.75 μT at 4.7 T, δamide = 3.5 ppm) from the empirical solution (Eq. (2)), as functions of T1w and T2w, for amide exchange rates of 30 and 10 s− 1, typical exchange rates under normal and acidic pH, respectively (Zhou et al., 2003). The experimental factor shows little change with relaxation and exchange rate, hence, can be treated as a constant that is near unity across the brain. Although APTR increases with exchange rate and hence pH,
Discussion
Our study demonstrated that the MRAPT analysis substantially enhances imaging specificity to ischemic acidification during acute stroke, permitting refined tissue classification. We found that diffusion lesion suffers more aggravated acidification than the perfusion/diffusion lesion mismatch. Importantly, the development of MRAPT analysis allows semi-automatic lesion segmentation, which refines the heterogeneous perfusion/diffusion mismatch into hypoperfused acidic lesion (Area IIa) and
Conclusion
Our study here shows that the proposed MRAPT MRI effectively minimized the non-acidosis related heterogeneity commonly observed in the routine pH-weighted MTRasym map, resulting in substantially enhanced pH specificity. We found that diffusion lesion suffered more aggravated acidosis than the perfusion/diffusion lesion mismatch. Importantly, the MRAPT analysis allows semi-automatic lesion segmentation, which refines the conventional perfusion/diffusion lesion mismatch into hypoperfused and
Acknowledgments
This study was supported by research grants from the National Natural Science Foundation of China81471721 (to Guo), National Science Foundation for Distinguished Young Scholars (to Ji), and the National Institutes of HealthR21NS085574 and R01NS083654 (to Sun).
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Current address: Department of Radiology, West China Second University Hospital, Sichuan University, China.